Typhoid conjugate vaccine: are we heading towards the elimination of typhoid in endemic countries?
Authors: Mohammad Tahir Yousafzai, Anita Elizabeth Heywood
Journal: The Lancet Global Health (2022)

Typhoid fever caused by Salmonella enterica serovar Typhi (S Typhi) is a serious public health problem in low-income and middle-income countries (LMIC). Globally about 11 million typhoid cases (predominantly among children younger than 15 years of age) and 116 000 related deaths occurred during 2017.1Stanaway JD Reiner RC Blacker BF et al.The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017.Lancet Infect Dis. 2019; 19: 369-381Summary Full Text Full Text PDF PubMed Scopus (268) Google Scholar Moreover, growing antimicrobial resistance including the recent emergence of extensively drug-resistant S Typhi is a growing threat that limits the available treatment options for typhoid fever in LMIC.2Qamar FN Yousafzai MT Dehraj IF et al.Antimicrobial resistance in typhoidal salmonella: surveillance for enteric fever in Asia project, 2016–2019.Clin Infect Dis. 2020; 71: S276-S284Crossref PubMed Scopus (16) Google Scholar, 3Yousafzai MT Qamar FN Shakoor S et al.Ceftriaxone-resistant Salmonella Typhi outbreak in Hyderabad City of Sindh, Pakistan: high time for the introduction of typhoid conjugate vaccine.Clin Infect Dis. 2019; 68: S16-S21Crossref PubMed Scopus (39) Google Scholar, 4Qureshi S Naveed AB Yousafzai MT et al.Response of extensively drug resistant Salmonella Typhi to treatment with meropenem and azithromycin, in Pakistan.PLOS Negl Trop Dis. 2020; 14e0008682Crossref Scopus (16) Google Scholar Although population-level public health measures to ensure safe drinking water, sanitation, and hygiene are a long-term solution to control typhoid, this requires a substantial amount of investment and long-term planning for countries with limited resources. Therefore, with the availability of low cost, highly effective, and safe typhoid conjugate vaccine, there is growing optimism regarding the elimination of typhoid fever in LMIC. Typhoid conjugate vaccine containing Vi polysaccharide conjugated to tetanus toxoid (Typbar TCV, Bharat Biotech International, Hyderabad, India) is a single-dose parental vaccine prequalified by WHO in 2017 and recommended for children as young as 6 months of age as well as for adults.5WHOTyphoid vaccines: WHO position paper, March 2018—recommendations.Vaccine. 2019; 37: 214-216Crossref PubMed Scopus (96) Google Scholar Like other conjugate vaccines, this typhoid conjugate vaccine has the ability to elicit T-cell response resulting in longer term protection against typhoid.6Vashishtha VM Kalra A The need & the issues related to new-generation typhoid conjugate vaccines in India.Indian J Med Res. 2020; 151: 22-34Crossref PubMed Scopus (5) Google Scholar In The Lancet Global Health, Nginache Nampota-Nkomba and co-authors7Nampota-Nkomba N Nyirenda OM Khonde L et al.on behalf of the Typhoid Vaccine Acceleration Consortium (TyVAC) teamSafety and immunogenicity of a typhoid conjugate vaccine among children aged 9 months to 12 years in Malawi: a nested substudy of a double-blind, randomised controlled trial.Lancet Glob Health. 2022; 10: e1326-e1335Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar report on the immunogenicity and safety of Typbar TCV among Malawian children. This was a substudy nested within a large, phase 3, double-blind, parallel arm, randomised controlled trial of Typbar TCV compared with meningococcal serogroup A conjugate vaccine (MCV-A) in healthy children aged 9 months to 12 years in Blantyre, Malawi. During 2018, 305 children were administered Typbar TCV and 297 children were administered MCV-A vaccine. Children aged 9–11 months were concurrently given measles vaccine. Immunogenicity was measured comparing Vi-IgG antibodies at baseline, 28 days, and between 730 and 1035 days after vaccination. Safety was measured using solicited and unsolicited local, systemic, and serious adverse events at different timepoints following immunisation. Among children vaccinated with MCV-A, the geometric mean titre (GMT) of Vi-IgG at day 0, 28, and between days 730 and 1035 remained unchanged (4·3, 4·4, and 4·6 ELISA units per mL, respectively); however, among children vaccinated with Typbar TCV, the authors reported more than a 500-fold increase in Vi-IgG GMT on day 28, followed by a decline resulting in about 11-fold higher than baseline titres between days 730 and 1035 (4·2 ELISA units per mL at baseline, 2399·8 on day 28, and 48·0 between days 730 and 1035). There was 99% seroconversion on day 28, which decreased to 80% between days 730 and 1035 among the Typbar TCV recipients. By contrast, there was only 0·4% seroconversion on day 28 and 4·4% between days 730 and 1035 among the MCV-A recipients. The authors reported no significant age-related differences (9–11 months, 1–5 years, and 6–12 years) within the recipients of Typbar TCV and MCV-A vaccines. Moreover, there was no interference observed between measles and TCV concomitant administration in the 9–11 month age group. The authors reported no significant safety issues attributable to Typbar TCV in this substudy. The observations were robust using per-protocol and intention-to-treat analyses. The results reported by Nginache Nampota-Nkomba and co-authors7Nampota-Nkomba N Nyirenda OM Khonde L et al.on behalf of the Typhoid Vaccine Acceleration Consortium (TyVAC) teamSafety and immunogenicity of a typhoid conjugate vaccine among children aged 9 months to 12 years in Malawi: a nested substudy of a double-blind, randomised controlled trial.Lancet Glob Health. 2022; 10: e1326-e1335Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar are consistent with those of previous clinical trials of Typbar TCV conducted in different regions including sub-Saharan Africa.8Mohan VK Varanasi V Singh A et al.Safety and immunogenicity of a Vi polysaccharide–tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study.Clin Infect Dis. 2015; 61: 393-402Crossref PubMed Scopus (120) Google Scholar, 9Shakya M Colin-Jones R Theiss-Nyland K et al.Phase 3 efficacy analysis of a typhoid conjugate vaccine trial in Nepal.N Engl J Med. 2019; 381: 2209-2218Crossref PubMed Scopus (93) Google Scholar, 10Qadri F Khanam F Liu X et al.Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial.Lancet. 2021; 398: 675-684Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar In Burkina Faso, a study of concomitant administration of Typbar TCV with measles vaccine among infants aged 9 months reported Vi IgG GMT of 1203·7 ELISA units per mL with 88% seroconversion on day 28 following immunisation. There were no safety issues or interference between measles vaccine and Typbar TCV observed among Burkinabe infants.11Sirima SB Ouedraogo A Barry N et al.Safety and immunogenicity of Vi-typhoid conjugate vaccine co-administration with routine 9-month vaccination in Burkina Faso: a randomized controlled phase 2 trial.Int J Infect Dis. 2021; 108: 465-472Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar Since the correlate of protection for typhoid conjugate vaccines is not yet available, it is difficult to assess the clinical significance of different levels of Vi-IgG antibodies on day 28 and between days 730 and 1035 following Typbar TCV immunisation reported by Nginache Nampota-Nkomba and colleagues. Well designed studies with longer follow-up, powered for the co-primary endpoints of immunogenicity and efficacy, and coupled with robust surveillance of laboratory-confirmed typhoid are critical to determine the duration and clinical significance of different levels of Vi-IgG antibodies following the single dose of Typbar TCV. Moreover, these studies will facilitate data-driven policy decisions on whether any additional primary or booster dose of Typbar TCV would be required in any age group to achieve maximum protection against typhoid throughout childhood. Hence, with availability of new data, filling knowledge gaps, and steering policy decisions to deploy Typbar TCV, the optimism that typhoid in LMIC can be eliminated is not far-fetched. AEH declares that she has received personal honoraria for presentation to roundtables from MSD and for feedback on educational material from Pfizer unrelated to this manuscript. MTY declares no competing interests. Safety and immunogenicity of a typhoid conjugate vaccine among children aged 9 months to 12 years in Malawi: a nested substudy of a double-blind, randomised controlled trialThis study provides evidence of TCV safety, tolerability, and immunogenicity up to 730–1035 days in Malawian children aged 9 months to 12 years. Full-Text PDF Open Access